Cookies

We use cookies to ensure that we give you the best experience on our website. You can change your cookie settings at any time. Otherwise, we'll assume you're OK to continue.

Durham University

Department of Biosciences

Profile

Publication details for Prof Roy Andrew Quinlan

Battaglia, Rachel A, Beltran, Adriana S, Delic, Samed, Dumitru, Raluca, Robinson, Jasmine A, Kabiraj, Parijat, Herring, Laura E, Madden, Victoria J, Ravinder, Namritha, Willems, Erik, Newman, Rhonda A, Quinlan, Roy Andrew, Goldman, James E, Perng, Ming-Der, Inagaki, Masaki & Snider, Natasha T (2019). Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander Disease severity. eLife 8: e47789.

Author(s) from Durham

Abstract

Alexander Disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.